UG Introductory Physiology 2024-3 PDF

Synapses Electrical: Structural continuity exists Chemical: No structural continuity exists  Synapses Chemical: No structural continuity exists Pre-synaptic terminals Synaptic vesicles (cluster in a region specialized for releasing neurotransmitters called active z...

Synapses Electrical: Structural continuity exists Chemical: No structural continuity exists  Synapses Chemical: No structural continuity exists Pre-synaptic terminals Synaptic vesicles (cluster in a region specialized for releasing neurotransmitters called active zone) Synaptic cleft Post synaptic terminal A chemical synapse can amplify the signal many times An example showing communications between neuron and astrocyte Neuromuscular Synapses: Ligand gated Na+ channels Voltage gated Na+ channels Morphologic types of Synapses: Type I – Usually excitatory Glutamatergic Type II – Usually Inhibitory such as GABAergic Direct and indirect gating Synaptic second messenger system cAMP system  Phosphatidyl inositol system  Memory Memory formation/acquisition and Structural plasticity Memory Consolidation Synaptic Plasticity , LTP (Long Term Potentiation) and additional forms of activity-dependent plasticity have been found, including long-term depression (LTD)19, EPSP-spike (E-S) potentiation20,21, spike-timing-dependent plasticity (STDP)22, depotentiation23–25 and de-depression25,26  During learning, reversible physiological changes in synaptic transmission take place in the nervous system, These changes must be stabilized or consolidated in order for memory to persist. The temporary, reversible changes are referred to as short- term memory (STM). Persistent changes as long-term memory (LTM). Molecular mechanisms involved in the initiation and maintenance of synaptic plasticity. Molecular mechanisms involved in the initiation and maintenance of synaptic plasticity a | Activity-dependent release of glutamate from presynaptic neurons leads to the activation of AMPA receptors (AMPARs) and to the depolarization of the postsynaptic neuron. Depolarization occurs locally at the synapse and/or by back-propagating action potentials (BPAP). b | Depolarization of the postsynaptic neuron leads to removal of NMDA (N-methyl-D- aspartate) receptor (NMDAR) inhibition, by Mg2+, and to Ca2+ influx through the receptor27. Depolarization also activates voltage-gated calcium channels, another source of synaptic calcium c | Calcium influx into the synapse activates kinases which, in turn, modulate the activity of their substrates. These substrates contribute to local changes at the synapse, such as morphological alteration through cytoskeletal regulation, or induce the transcription of RNA in the nucleus by regulating transcription factors (TFs). d | Transcribed mRNA is translated into proteins that are captured by activated synapses and contribute to stabilization of synaptic changes. VGCC, voltage-gated calcium channel. LTP or Learnining induces morphological changes in dendritic spines. a. Increase in spine head volume. b. Spine perforation c. Increase in the Number of spines And in the number of multiple spine boutons Visualization of new dendritic spine growth following LTP or Learning Detection of perforated spines and multiple spine boutons (MSB) after LTP using electron microscopy Detection of perforated spines and multiple spine boutons (MTB) after LTP Detection of changes in spines 24 hr after learning  Detection of changes in spine after 24 hrs of learning. (trace eye blink conditioning) The cytoskeleton and structural changes Long-term potentiation (LTP) and behavioural experience induce glutamate receptor trafficking into spines  Activation of extracellular signal- regulated kinase (ERK) by synaptic signalling, and downstream targets. a | Calcium influx, either through NMDA type glutamate receptors (NMDARs) or voltage- gated calcium channels (VGCCs) triggers an increase in the levels of Ras–GTP. This leads to the activation of Raf, mitogenactivated protein kinase (MAPK)/ERK kinase (MEK) and ERK, allowing phosphorylation of both nuclear and cytoplasmic ERK substrates. The precise route to Ras activation might differ depending on the neuronal cell type and/or the extracellular stimulus. b | Following its activation, ERK phosphorylates extranuclear targets such as the voltage- dependent K+ channel KV4.2 and downstream kinases such as ribosomal protein S6 kinases (RSKs). A pool of activated ERK and RSK translocates to the nucleus, where ERK phosphorylates and activates the constitutively nuclear mitogen- and stress-activated kinases (MSKs). In the nucleus, ERKs, RSKs and MSKs phosphorylate transcription factor substrates. The best-characterized of these substrates is CREB (cyclic- AMP-responsive element (CRE)-binding protein), which might be phosphorylated by MSKs, RSKs or both. It is highly unlikely that this figure represents the entire range of neuronal ERK/RSK/MSK targets, and the identification of further substrates will be of great interest.  b | Impaired performance of MEK inhibitor-treated animals in a water maze task. Mice given an intraperitoneal injection of the MEK inhibitor SL327 or vehicle control were placed in a water maze containing a hidden escape platform. The mice could learn the location of the platform by reference to distal visual cues. Both SL327- and vehicle-treated animals learned to find the platform following training. The platform was then removed and the mice were subsequently tested for their ability to remember the previous position of the platform. The figure shows a trace of the swim path of a vehicle-treated mouse and an SL327-treated animal. The vehicle-treated animal searched intensely in the area of the maze where the platform was previously positioned (the top right quadrant, viewed from above). However, the SL327- treated mouse searched aimlessly around the pool and seemed unable to remember the location of the platform. c | Ras-dependent increases in AMPAR transmission are blocked by MEK inhibitors. Infection of organotypic hippocampal slices with Sindbis virus expressing Ras(ca)–GFP (a GFP-tagged constitutively active Ras) caused an increase in AMPAR-mediated synaptic transmission in infected cells. This increase was prevented by the MEK inhibitor PD 98059, but was unaffected by the p38 MAPK inhibitor SB 203580 (upper panel). The active Ras construct did not alter NMDAR (N-methyl-D-aspartate receptor)-mediated transmission (lower panel). Importantly, the authors also demonstrated that Ras(ca)–GFP expression occludes subsequent pairing-induced LTP in infected cell Axoplasmic Transport Anterograde and Retrograde Fast and Slow transport  The axonal transport: Who does the action? Kinesin superfamily proteins (KIFs) and dynein superfamily proteins are microtubule-dependent motors that slide along microtubules  Axonal transport delivers proteins, lipids, mRNA and mitochondria to the distal synapse and clears recycled or misfolded proteins. Such transport is involved in neurotransmission, neural trophic signalling and stress insult responses. Cargoes are conveyed along the microtubule tracks in axons by motor proteins. Disturbances in axonal transport are key pathological events that contribute to neurodegeneration in Alzheimer's disease, polyglutamine diseases, hereditary spastic paraplegia, Charcot–Marie–Tooth disease, amyotrophic lateral sclerosis and Parkinson's disease. The identification of mutations in genes encoding motor proteins in patients with neurodegenerative diseases strongly supports the view that defective intracellular transport can directly trigger neuron degeneration. Axonal transport deficits might arise through various mechanisms, including defects in cytoskeletal organization, impairment of motor protein attachment to microtubules, altered kinase activities, destabilization of motor–cargo binding and/or mitochondrial energetic breakdown. Autophagy and RNA metabolism might also interfere with the efficiency of axonal transport.